I just came across this passage in Phinney and Vovek's The Art and Science of Low Carbohydrate Living that explains keto adaptation:

Quote:

“Beta-hydroxybutyrate and acetoacetate are made in the liver in about equal proportions, and both are initially promptly oxidized by muscle. But over a matter of weeks, the muscles stop using these ketones for fuel. Instead, muscle cells take up acetoacetate, reduce it to betahydroxybutyrate, and return it back into the circulation. Thus after a few weeks, the predominant form in the circulation is beta-hydroxybutyrate, which also happens to be the ketone preferred by brain cells (as an aside, the strips that test for ketones in the urine detect the presence of acetoacetate, not beta-hydroxybutyrate). The result of this process of ketoadaptation is an elegantly choreographed shuttle of fuel from fat cells to liver to muscle to brain.”[1]

I don't think there could be much more proof that ketosis is not a pathological condition!

BTW, I highly recommend this book. Phinney and Volek are two of the premier researchers in this space, and this book is meant to be a solid overview for both individuals and doctors.

Yep. One of many reasons I only eat off plan twice a year or so. I have been keto-adapted for months now, and I plan to be that way (with very rare exceptions) for the rest of my life. I strongly believe that it has helped me continue to lose (albeit slowly) during the months I've had some difficult health issues and been on meds that are notorious for causing weight gain.

And if anyone hasn't seen Dr. Phinney's talks and interviews on YouTube, I highly recommend them as companions to the book.

I am in the middle of reading The Art and Science of Low Carbohydrate Living right now and it's a great book. I know Why We Get Fat get recommended frequently here, and that's a great book too, but for anyone looking for something else to read following WWGF, or even an alternative, I cannot recommend it highly enough. It has a similar easy reading style, and it doesn't shy away from medical facts, though it makes them easy to understand. In fact, I plan to try and finish it over this long weekend. And keep implementing its recommendations!

I agree with all the recommendations. If you are compulsive like me, Wheat Belly also has some interesting information. I feel like Fat Chance and Wheat Belly together offer a pretty clear view of the problems with carbs. The Art and Science is nice because it also discusses a lot of Phinney and Volek's research.

Another interesting book, not for the science but for the evil ways of Big Food, is Sugar, Salt, Fat. It discusses, with some whistleblower-type sources, the way Big Food uses those three ingredients to make you crave the dog crap they produce.

I would also like to point out something that is frequently overlooked. The most significant long-term adaptation to the dramatic restriction of dietary carbohydrates comes when skeletal muscle becomes able to directly burn fatty acids as fuel, rather than using ketones, which is *why* (as noted in the passage you've cited) skeletal muscle returns BOHB to the bloodstream for use by the brain. Phinney and Volek point out this aspect of the adaptation in another of their books, The Art and Science of Low Carbohydrate Performance. I think the authors cover this adaptation to fatty acids more clearly in the "performance" book because of the adaptation's specific advantages for athletes.

Once the process of keto-adaptation is complete (which takes from a few weeks to a month), muscle both at rest and during exercise comes to rely heavily on fatty acids. This adaptation of the muscle away from ketone use spares hepatic ketone production for use by other tissues, especially the brain.

This is a key point. Practically speaking, the brain can burn only glucose or ketones. On a very low carbohydrate diet, the brain comes to rely on ketones as its primary fuel. Although ketones are preferentially taken up by the brain, because of the large mass of skeletal muscle and the increase in blood flow to active muscles during exercise, this delayed shift of the muscles away from ketones and toward fatty acid use is vital to preserving fuel flow to the brain during exercise in the keto-adapted athlete. In part, the time it takes the body to choreograph these changes in whole body fuel flow explain why keto-adaptation takes a couple of weeks rather than just a few hours or days.

From chapter 3 of The Art and Science of Low Carbohydrate Performance, "A Tectonic Shift in Thinking"

I don't want to step on your original point, which is a good one. But I think this information about skeletal muscle gets overlooked a lot. And I think the omission of this information from a lot of the popular low-carb diet literature causes some confusion about *why* keto-adaptation takes several weeks, rather than more closely following the initiation of ketosis. And it also explains *why* the body produces fewer ketone bodies after the process of keto-adaptation has been completed.

If you would be interested in reading an extremely interesting (in my opinion) and relatively short piece on ketones and fuel metabolism, I would highly recommend this article by George F. Cahill, Jr:

Cahill is an old school scientist. He was one of the world's leading experts on metabolic pathways (he died in 2012) and Cahill's research on glucose metabolism significantly advanced diabetes research in the 20th century. The linked article isn't just about metabolism, though, it's also quite a charming retrospective of Cahill's career. With regard to the reasons that ketosis is absolutely not a negative medical condition, Cahill notes in this article that the brains of newborn human infants are significantly fueled by ketones and that ketosis is a natural part of human metabolism and is, in fact, one of the mechanisms that has helped our species survive:

Not well known, however, is the metabolism of the human newborn, which is essentially ketotic. Blood glucose levels fall strikingly in the neonate, and concentrations of βOHB may rise to 2–3mM. The newborn human brain consumes 60%-70% of total metabolism at birth, nearly half via β-hydroxybutyrate. Fitting in with this pattern is maternal colostrum. It contains much triglyceride and protein, but little lactose, starting man's entry into society on an Atkins diet!

This article is about fuel metabolism in *starvation*. So I would like to note that most of the information that we have on keto-adaptation actually comes from the body of medical research on starvation. We have decades of extremely well-structured clinical studies into the process by which the body's internal mechanics change in response to periods of fuel deprivation. And these studies of metabolic fuel pathways are directly applicable to ketogenic dieting because dramatically restricting the intake of dietary carbohydrates exactly *mimics* the fuel adaptation processes that occurs when the body is completely deprived of food. The restriction of dietary carbohydrates is not a *negative* state, like total starvation, but it has a similar effect of changing the body's primary fuel use from significantly relying on glucose as fuel to relying primarily on fat as fuel.

I have this nagging question in the back of my mind and this seems like a good place to ask it.

Suppose one gets all the way to the point where the body is primarily relying on fat for its fuel, as you have mentioned. And then, you eat 1 cup of Haagan-Dazs ice cream ( 40g Carbohydrate ) and a couple of peanut butter cookies ( 30g Carbs) , maybe once or twice a week.

Do you drop out of this ketogenic state and have to go weeks on low carbs again or does your body just store the extra glucose as fat, soon to be burned off like all others.

This is a pretty important question to me, I hope you get the drift of what I am trying to ask.

If you eat that, you'll almost certainly have kicked yourself out of ketosis. That means the body will address the glucose first, burning it if possible, storing it if not. Then you'll spend at least a few days getting yourself back into ketosis, only to repeat the process. And if you do that with any kind of regularity, you'll lose out on being ketoadaptated at all. You wouldn't be giving your body the uninterrupted time in ketosis to become ketoadaptated in the first place.

But being ketoadaptated doesn't give one carte blanche to eat unlimited carbs.

I have this nagging question in the back of my mind and this seems like a good place to ask it.

Suppose one gets all the way to the point where the body is primarily relying on fat for its fuel, as you have mentioned. And then, you eat 1 cup of Haagan-Dazs ice cream ( 40g Carbohydrate ) and a couple of peanut butter cookies ( 30g Carbs) , maybe once or twice a week.

Do you drop out of this ketogenic state and have to go weeks on low carbs again or does your body just store the extra glucose as fat, soon to be burned off like all others.

This is a pretty important question to me, I hope you get the drift of what I am trying to ask.

All answers and opinions welcome!

This is an extremely complicated and important question!

The distinguishing factor of keto-adaptation is the shift in muscle tissue to a state in which skeletal muscle can directly and readily burn fatty acids as a primary fuel. That adaptation process takes several weeks because the fuel-burning engines in muscle cells have to be re-engineered to primarily burn fatty acids. Starvation studies show that the *average* amount of time this process takes is 3 weeks. However, the level of insulin resistance in muscle cells determines the conversion time -- less insulin-sensitive cells take a longer time to convert -- so some individuals can take MUCH longer than 3 weeks to adapt.

And the adaptation process doesn't happen to all of the cells at the same time. The conversion process happens in stages, with more cells being converted as time passes. For example, on the first day after liver glycogen has been depleted, some cells are converted. A week after liver glycogen has been depleted, a larger percentage of muscle cells have been converted. And three week after liver glycogen has been depleted (in a typical study subject), most of the skeletal muscle has been converted. And this is further complicated by the fact that some cells in an individual body are more insulin-resistant than other cells, so some cells may remain unconverted for a long time after the rest of an individual's muscle tissue has been converted.

Athletes are a *special* population that has some additional advantages in this process. Unlike most humans who have average to lower-than-average stores of bodyfat, athletes often have large stores of "intramuscular trigylcerides" (IMTG) that their muscles use to fuel performance. IMTGs are sort of like the "marbling" that you see in a steak, it's fat that is stored inside muscle tissue instead of being stored with larger deposits of their bodyfat.

Typically, only obese individuals and trained athletes store IMTG. In obese individuals, IMTGs are associated with insulin resistance (partly) because the increased concentration of fat depresses the insulin sensitivity of muscle cells. In athletes, however, because their bodies have developed a process that involves the regular use of IMTG metabolism in muscle tissue, athletes also produce larger than normal amounts of "sterol regulatory element-binding proteins" (SREBP), which prevents the IMTGs from causing insulin resistance in their muscle cells and gives them a fat-metabolizing fuel advantage. It's somewhat difficult to do large-scale studies in humans because the biopsies and evaluation processes are so invasive, but hormone testing, in vitro studies, and animal models demonstrate some of the ways that the muscle tissue of athletes has a slightly different adaptation to fat as muscle fuel.

In summary, SREBP-1 protein and SREBP-1c mRNA are increased in interventions that increase IMTG despite enhanced insulin sensitivity. CR and exercise-induced augmentation of SREBP-1 expression may be responsible for the increased IMTG seen in skeletal muscle of highly conditioned athletes.

Exercise also enhances insulin sensitivity in muscle cells. So athletes that train regularly have a higher than average level of insulin sensitivity in their muscle tissue and should show a faster adaptation rate when the body re-engineers to burn fat as a different primary fuel.

Also, muscle glycogen is not as easily depleted as liver glycogen. The state of "ketosis" is induced when LIVER glycogen is depleted, which typically happens quite quickly in most bodies, but the body can still be in a state of ketosis for a significant amount of time while MUSCLE glycogen is still stored at substantial levels. Muscle glycogen is (basically) reserved for the use of muscle tissue so the muscle glycogen stores can (basically) only be depleted by exerting the muscles in a way that causes them to draw upon and exhaust their stored glycogen. So athletes that exert their muscles through training can/should/will deplete their muscle glycogen stores at a faster rate than a less active person, which means the process of keto-adaptation in muscle tissue can/should/will start sooner in an athlete's muscle cells.

Before bodybuilders start a "ketogenic cycle," they do what is called a "full-body depletion workout" in order to empty the muscle glycogen stores. Muscle glycogen can never be *completely* depleted because the "Krebs Cycle" and "Cori Cycle" and other quite complicated systems of metabolic fuel processing replenish *some* muscle glycogen even when no food -- at all -- is fed to the body. But the process of keto-adaptation doesn't depend on ALL of the muscle glycogen being depleted, although *substantial* depletion supports a faster adaptation process.

But the situation is further complicated because this adaptation is not *only* about the muscle cells. The state of the liver determines the body's primary fuel processing system. This means that once the liver has exhausted it's store of glycogen, the liver's fuel processing system begins to convert fat into ketones to feed the body, and the production of ketones STARTS the keto-adaptation process. As noted above, the keto-adaptation process takes several weeks.

However, the reverse process of switching the body back to being a primarily glucose-burning engine happens almost immediately. It takes the liver a minimum of 5 hours to up-regulate the enzymes that process glucose as fuel -- and the liver will continue to produce ketones during this period. HOWEVER, the process of changing back to processing glucose as a primary fuel starts immediately when a significant enough amount of dietary carbohydrates are re-fed into the body. It takes a minimum of 5 hours for the metabolic effects to register but once the process has been initiated by the introduction of a significant supply of glucose, the keto-adaptation process ends. The muscle cells that had been burning fat as their primary fuel -- and that took several weeks to adapt to a primary state of fat burning -- can IMMEDIATELY return to burning glucose as their primary fuel. But the process to re-adapt to burning fat as their primary fuel will take another minimum of several weeks, just as it did the first time keto-adaptation was initiated.

It's impossible to say how many dietary carbohydrates will force an individual body out of keto-adaptation. The amounts vary depending on the individual metabolism and there haven't been enough large-scale studies to determine guidelines or averages. And ketosis is not a good enough guideline because the body can continue to produce ketones while the metabolic systems are changing. Bodybuilding "cutting" diets work because they maintain fat-burning and ketone production while carbs are re-fed into the body to re-fill muscle glycogen stores. So we know, from testing bodybuilders, that they can do high-carb re-feeds for 5-36 hours (depending on which type of diet they're following and on their starting level of lean body mass) and that their bodies can continue to produce ketones and continue to burn fat as their primary fuel even when large amounts of dietary carbohydrates are re-fed.

Unfortunately, this information from bodybuilding practice can't be applied to the typical dieter. For one thing, all of the advantages (noted above) that athletes have in terms of changing fuel processing systems can't be applied to a *normal* dieter. Also, because bodybuilding ketogenic diets regularly re-feed dietary carbohydrates, they reverse the liver's metabolism at least once per week, which means that bodybuilders don't become keto-adapted during their ketogenic cycles.

So the short answer -- after all of that build up -- is that eating a sufficient amount of dietary carbohydrates to end keto-adaptation means that the body will take a minimum of several weeks to re-adapt.

Trillex, we seem to be working like a tag team. We often say the same thing in different language.

I love reading your posts; you come at a lot of the same information through a different lens, which helps me to clarify my own interpretations.

HaHa! I know that I'm like a storehouse of strange details. And although the details initially seem to be only tangentially related, somehow they always systematically lead back to the world of competitive bodybuilding. If you put all of my posts together, they would probably be like a DaVinci Code that reveals the secret to winning a major IFBB contest...

Seriously though, I just wrote in my diary that I am following a strategy with little scientific evidence ( depriving the body of all carbs and as much protein as I can without depriving it between the hours of 5 pm and 11 pm the next day)
If I read again and again what you all wrote I might get around to evidencing it a bit better.

Just another thought, don't you just love when (mostly slim)people tell you that if we only took the trouble to reduce our fat intake it would be more beneficial to us than lowcarb,that we are doing damage to our body and we would be slim . How would this be for a comeback?

What ??? And rob my brain of beta-hydroxybutyrate ? Do you know what you are suggesting ???

There's plenty of scientific evidence in favor of low carb, high fat diets; there is just little bureaucratic consensus. That low fat diets are so "healthy" is what has little evidence: no link between saturated fats and heart disease; string link between carb intake and insulin resistance, fatty liver disease, inflammation, and other problems; more weight lost and kept off on low carb diets; etc.

The quote in OP sure puts a nail in the coffin regarding the suggestion that regular high carb indulgences (say once a week or once a month) are fine for LCers.

I've got The Art and Science of Low Carbohydrate Living on my Amazon Wish List. I know it is a book I'll turn to over & over so I want the paper version rather than the Kindle one.

The more I learn about health & nutrition the more there is to learn. Always more informative books to read. I'd already stopped eating wheat by the time I read Wheat Belly but I still found the information in it valuable.

I haven't read Sugar, Salt, Fat yet but I'm sure I will get a lot out of it, too. I do not eat processed foods so I know first-hand the difference it makes in how I feel. It is horrible what is passed off as food these days.

Trillex, The Art and Science of Low Carbohydrate Performance sounds excellent, too. Thanks for mentioning it. It sounds like another must-read for me.

There's plenty of scientific evidence in favor of low carb, high fat diets; there is just little bureaucratic consensus. That low fat diets are so "healthy" is what has little evidence: no link between saturated fats and heart disease; string link between carb intake and insulin resistance, fatty liver disease, inflammation, and other problems; more weight lost and kept off on low carb diets; etc.

Exactly.

It is all about money.

I'm always researching health & nutrition and just when I think it couldn't get any worse it does. Most everything I read supports the health benefits of LC nutrition. Studies show LC nutrition is very healthy & healing. Those studies are regularly ignored because the results are not what the researchers wanted to hear so the studies must be wrong. As a result, most of the time the recommendation from medical professionals is to eat low fat, high carbs. Oh, and take drugs. Lots of drugs.

Trillex, thank you for the link to George F. Cahill article. Very interesting stuff (although much is far above my head). However, I am enjoying the challenge!

I'm glad you're enjoying it!

I LOVE the way Cahill describes the many things they didn't know -- like the belief that enzyme activity was an essentially stable process in humans, or how they didn't understand the ways that insulin functioned in a fasting/starving body. I'm just totally in love with the culture of creativity and curiosity that he describes! And the collegiality among their research community. There's a lot of science and metabolic details in the article but, at its core, I think this is a very compelling story about how much can be gained from a lifetime of curiosity and investigation. I've read a lot of things that have made me awestruck about the human body, but this piece makes me awestruck about the human desire to explore. Cahill is definitely on my list of people to have coffee with in the afterlife!

Trillex, I just got around to reading the articles you cited. Highly interesting reading, better than a crime novel. If you had anything else of that nature I would be most happy to read it. If you have the time could you share it with me? I had never heard of Cahill, but will now actively look for more of his stuff as I cannot get the book here.

Trillex, I just got around to reading the articles you cited. Highly interesting reading, better than a crime novel. If you had anything else of that nature I would be most happy to read it. If you have the time could you share it with me? I had never heard of Cahill, but will now actively look for more of his stuff as I cannot get the book here.

I'm so excited that you're interested!

I think Cahill's article, "Fuel Metabolism In Starvation," is somewhat unique because of the way that Cahill has integrated so many fascinating details from his career into an overview of fuel metabolism. I don't think most of the studies are quite as compelling because I don't think most research reports have that level of style and skill at storytelling.

But Cahill actually has an even more comprehensive piece called "Starvation In Man," which he published in 1970. Unfortunately, the full article is not available for free online. The ladies at the research library, here, have accounts to the different online research services and they printed out the text for me. But I'm not sure if all libraries will do that. But here is the citation, in case your local library can print it up for you:

Here is a link to what I think is a FANTASTIC overview of metabolic fuel interactions! Philip J. Randle is an old school scientist, like Cahill. Randle's research established the mechanisms of the glucose-fatty acid cycle in fuel metabolism, and opened the door to a lot of important discoveries about the role of hormones in metabolic fuel use -- among other things, Randle basically figured out why obese individuals become insulin resistant. Here is a research overview from 2009 that starts with Randle and looks at where Randle's work in the 1960s has led our current understanding of the relationship between hormones and fuel substrates. I really enjoyed this piece because it reminds us that our understanding of physiology is still evolving because we are such intricately complicated machines:

Here, we review the known short- and long-term mechanisms involved in the control of glucose and fatty acid utilization at the cytoplasmic and mitochondrial level in mammalian muscle and liver under normal and pathophysiological conditions. They include allosteric control, reversible phosphorylation, and the expression of key enzymes. However, the complexity is formidable. We suggest that not all chapters of the Randle cycle have been written.

And here is one of the most fascinating studies of starvation, in my opinion, because it looks at the mechanics of fuel processing and asks the essential question of *why* the human body will die of starvation when ample amounts of bodyfat are still available as a fuel source:

The purpose of this work was to clarify the essentiality of glucose production from amino acids in obese subjects undergoing prolonged starvation and to provide an explanation for death after the depletion of lean body mass when some body fat is still available to meet body energy requirements.

Here is another very interesting study that looks at the interchange between glycogen depletion and fat oxidation rates in obese subjects. Glycogen depletion -- accomplished through exercise -- increases the rate at which the body will burn fat, which is why bodybuilders do full-body glycogen-depletion workouts before their ketogenic "cutting" cycles:

With the HF treatment, fat oxidation was below fat intake, indicating the slow change of oxidation to intake on an HF diet. After the HF + Ex treatment, however, fat oxidation matched fat intake. In conclusion, obese subjects are capable of rapidly adjusting fat oxidation to fat intake when glycogen stores are lowered by exhaustive exercise.

Also with regard to glycogen depletion, this really important study helped to define the mechanism on which bodybuilding re-feeds operate. Researchers looked at what the body actually does with glucose when dietary carbohydrates are fed into a glycogen-depleted body:

The studies on humans are the most relevant because, in many ways, our metabolisms operate somewhat differently than other mammals. So I won't bore you by listing a bunch of animal studies. But I've recently been reading a lot of studies that were done on rats and I am FASCINATED by them! Because rats will, apparently, drop bodyfat like crazy no matter what intervention is done with them. I honestly believe that rats lose bodyfat as the result of stress, and that scientists stress rats out, so the rats lose bodyfat no matter what the researchers do to them. It's pretty hilarious because there are a lot of compounds that cause rats to quickly lose a huge percentage of their bodyfat, but then the human body has absolutely no response to similar doses of the same compounds. I actually find it kind of hilarious!

Thank you,thank you thank you ! It is a rainy day here so your timing could not be more perfect.
I have always been interested but stopped reading. My interest renewed itself when my "onset of age" symptoms have all but disappeared . (The tension in my neck and shoulders and my chronic ankle pain for example) I had never made the connection before.So now I read in various languages as research and emphasis varies.
You are a star !

Amazing about the rats. Could I be one let´s say for a week ? That would do me.
I suppose we have no choice than to presume that some things are similar and will work in humans until it actually gets to test stage but until now nothing seems to have worked as it works for them in spite of headline grabbing announcements .

I love being informed about how things work and why. I have rarely been ketoadapted in the many years I have been low carbing. Frankly it's because I eat off-plan rather regularly. I'm OK with the consequences of that, and this woe works for my life and health right now. If things change, I know enough to tweak.

HaHa! I know that I'm like a storehouse of strange details. And although the details initially seem to be only tangentially related, somehow they always systematically lead back to the world of competitive bodybuilding. If you put all of my posts together, they would probably be like a DaVinci Code that reveals the secret to winning a major IFBB contest...

Thank you,thank you thank you ! It is a rainy day here so your timing could not be more perfect.
I have always been interested but stopped reading. My interest renewed itself when my "onset of age" symptoms have all but disappeared . (The tension in my neck and shoulders and my chronic ankle pain for example) I had never made the connection before.So now I read in various languages as research and emphasis varies.
You are a star !

I don't want to keep throwing random readings at you! But I think you might also be interested in this paper from a lecture by Daniel W. Foster. Foster is one of the world's great physician-biochemists -- who defined one of the mitochondrial regulatory systems for fatty acid oxidation and ketogenesis -- and this is a WONDERFUL piece on glycogen, ketogenesis, and the metabolic fuel cycle:

I found it SUPER interesting because he clarifies a lot of points that directly relate to the structure of bodybuilding "cyclical ketogenic diets" (CKD). For example, fructose is the last type of sugar that is re-fed on a CKD because fructose preferentially refills liver glycogen (sucrose is also saved for the end of the re-feed cycle because sucrose is half fructose). Glucose (or dextrose) -- as used in the early stages of a CKD re-feed -- will preferentially refill muscle glycogen stores, without refilling liver glycogen until the muscles are re-compensated. The goal of a CKD re-feed is to "super-compensate" muscle glycogen, and Foster explains how fructose phosphorylation activates enzymes in the liver that start the process of re-compensation of liver glycogen. This is the process that limits muscle glycogen compensation -- and inhibits muscle glycogen super-compensation -- which is why bodybuilders save fructose (and sucrose) for the end of the re-feed.

The whole paper is just generally very interesting! It's a fascinating look at operations of the human body while fasting. And Foster details the research that explains how and why a lot of human glycogen synthesis depends on indirect metabolic pathways.